It is well reported in the literature that essential fatty acids (EFAs) of the n-3 and n-6 unsaturation pattern have beneficial effect in a wide variety of human physiological disorders. WO 02/02105 (Laxdale Limited) describes their beneficial use for an extremely wide range of diseases and as a general nutritional supplement. Harbige (1998) Proc. Nut. Soc. 57, 555-562 reviewed the supplementation of diet with n-3 and n-6 acids in autoimmune disease states, and particularly noted evidence of benefit of γ-linolenic (GLA) and/or linoleic acid (LA) rich oils, such as borage oil, in reducing clinically important signs and symptoms of rheumatoid arthritis.
Two studies on multiple sclerosis (MS) patients are noted that indicate that relapse and severity of the disease might be reduced by treatment with oils containing n-6 acid moieties (Miller et al (1973) and Bates et al (1978)), but a further study failed to confirm this effect (Paty et al (1978). These papers report that supplementation of human patients with about 20 g/day of linoleic acid (18:2n-6) affected duration and severity of relapses of multiple sclerosis such that relapses were less frequent, less severe and of shorter duration than controls. Bates noted that a mixture of linoleic acid and γ-linolenic acid had been suggested back in 1957 to be possibly more efficacious in treating inflammation and autoimmune diseases and set out to investigate this in the trial. However, it was found that where this combination was tried, at 3 g oil per day (Naudicelle Evening Primrose oil) patients who had relapses became more ill on the trial oil than on the control.
Meta analysis of these linoleic acid studies by others (Dworkin et al (1984)) demonstrated reduced relapse rate and severity with a decrease in the degree of long-term progression of the disease in patients with mild multiple sclerosis. Later open studies of patients with multiple sclerosis suggest that low fat diet and/or manipulation of dietary n-3 and n-6 fatty acids may be beneficial (Swank & Grimsgaard (1988); Harbige et al (1990).
Although the aetiology of MS remains unknown, strong evidence suggests the presence of autoimmune mechanisms in the disease pathogenesis [Martino & Hartung 1999]. Studies have shown that MS patients have a much higher number of neuro-antigen e.g. myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) autoreactive T-cells which are in an increased state of activation compared with healthy controls [Fredrikson et al 1994, Kerlero de Rosbo et al 1993, 1997, Chou et al 1992, Ota et al 1990, Burns et al 1999, Zhang et al 1994, Tejada-Simon et al 2001]. The actual processes of axonal damage e.g. chronic inflammation, demyelination and astrogliosis in MS is complex but white matter inflammation and demyelination are considered to determine disease severity, whilst recent studies suggested that axonal damage in MS begins in the early stages of the disease and contributes to disability (De Stefano et al, 2001).
Experimental autoimmune encephalomyelitis (EAE) is the most frequently used animal model for immune mediated effects of MS. Studies in the guinea-pig have shown that linoleic acid partially suppresses the incidence and severity of EAE (Meade et al (1978)). Using γ-linolenic acid-rich oils from fungal or plant sources, complete protection was demonstrated in both rats and mice (Harbige et al (1995), 1997b). These investigations demonstrated disease modifying effects of linoleic acid and γ-linolenic acid on clinical and histopathological manifestations of EAE. Depending on dose, γ-linolenic acid was fully protective in acute rat EAE whereas linoleic acid had dose-dependent action on the clinical severity but did not abolish it.
Despite these experimental findings, it is recognised that the human disease, multiple sclerosis, is highly complex and can be conversely exacerbated and ameliorated by the activity of T-cells and other immune response factors. It is thought that the n-6 fatty acids promote autoimmune and inflammatory disease based upon results obtained with linoleic acid only. TGF-β and PGE2 production has been shown to be increased non-specifically in γ-linolenic acid fed mice ex vivo; but whilst TGF-β has been reported to protect in acute and relapsing EAE ((Racke et al (1993); Santambrogio et al (1993)), PG inhibitors such as indomethacin augment, and thus worsen, the disease (Ovadia & Paterson (1982)).
Cytokines are implicated in the pathogenesis of MS, with many studies showing an increase in myelinotoxic inflammatory cytokines (TNF-α, IL-1β and IFN-γ) coinciding with the relapse phase of the disease. Conversely, levels of the anti-inflammatory and immunosuppressive cytokine transforming growth factor-beta1 (TGF-β1) appear to be reduced during a phase of relapse and increase as the patient enters remission. Thus the balance between biologically active TGF-β1 and the pro-inflammatory TNF-α, IL-1β and IFN-γ appears to be dysregulated during MS relapse-remission.
During natural recovery phase from EAE, TGF-β-secreting T-cells inhibit EAE effector cells, TGF-β is expressed in the CNS and, in oral-tolerance-induced protection in EAE, TGF-β and PGE2 are expressed in the brain (Karpus & Swanborg (1991); Khoury et al (1992)). Harbige ((1998) concluded that dietary γ-linolenic acid effects on EAE are mediated through Th3-like mechanisms involving TGF-β and possibly through superoxide dismutase antioxidant activity.
It has been suggested to use, inter alia, γ-linolenic acid and linoleic acid rich Borage oil as a means to provide immuno-suppression in multiple sclerosis (U.S. Pat. No. 4,058,594). The dose suggested is 2.4 grams of oil per day and no actual evidence of efficacy is provided.
Borage oil (typically 23% γ-linolenic acid and 37% linoleic acid per 100% fatty acid content) has been shown to significantly reduce clinically important signs and symptoms of autoimmune disease associated with active rheumatoid arthritis (Leventhal et al (1993)). Borage oil and fungal oil (see FIG. 1) have been shown to be effective in the EAE animal model use to identify MS candidates, whilst never having been shown to be significantly effective in the human disease. High levels of linoleic rich oil containing low levels of γ-linolenic acid (EPO: linoleic acid:γ-linolenic acid 7:1) partially suppressed the incidence and severity of EAE in rat (Mertin & Stackpoole, 1978) whereas the Naudicelle study referred to above led to worsening of patients. In spite of the use of Borage oil and other GLA/LA containing oils such as Evening Primrose oil by multiple sclerosis sufferers over the past 30 years or so, the vast majority of patients fail to recover from the disease, showing no significant improvement, with the underlying disease continuing to progress to death.
Other more dramatic immunosuppressant treatments, including T cell depleters and modulators such as cyclophosphamide, are also shown to be effective in the EAE model, but where these are employed in the human multiple sclerosis disease symptoms improve, but the underlying disease continues to progress. T-cells indeed produce beneficial cytokines, such as TGF-β1, as well as deleterious ones in man. David Baker of Institute of Neurology, UK summed up the disparity between what is effective in the EAE and in MS with a paper entitled ‘Everything stops EAE, nothing stops MS’ at the 10th May 2004 UK MS Frontiers meeting of the UK MS Society.
It is clear that immunosuppression alone cannot cure MS. This is almost certainly due to a fundamental underlying metabolic disorder in MS patients that leads to membrane abnormality, cytokine dysregulation and subsequent immune attack and lesioning. Although patients go into remission in relapse-remitting disease, the underlying demyelination proceeds.
The ‘gold standard’ treatment for MS remains interferon, such as with β-Avonex®, Rebif® and other interferon preparations. This gold standard treatment only addresses needs of some, eg 30%, of the patients and even in these symptom improvement is restricted to reduced severity of relapses. Whilst symptoms may be reduced in a proportion of patients, the disease tends to progress to further disability and death due to underlying degeneration.